18 November, 2013

The WHI database will probably provide an infinite number of publications. This time the focus of the analysis was to explore whether pretreatment levels of sex hormones modify the effect of estrogen + progestin (E+P) on breast cancer [1]. This was a nested case–control study within the WHI randomized clinical trial of E+P. The trial enrolled 16,608 postmenopausal women aged 50–79 years with an intact uterus and no breast cancer history. During a mean of 5.6 years of follow-up, 348 incident breast cancer case subjects were identified and matched with 348 control subjects. Case and control subjects had their sex hormone levels measured at baseline (estrogens, testosterone, progesterone and sex hormone binding globulin (SHBG)) and at year 1 (estrogens and SHBG) using sensitive assays. Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol (p trend = 0.04), bioavailable estradiol (p trend = 0.03), estrone (p trend = 0.007), and estrone sulfate (p trend = 0.007). E+P increased all measured estrogens and SHGB at year 1 (all p < 0.001). The effect of E+P on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol and estrone were in the lowest quartiles. For example, the odds ratio for E+P relative to placebo was 2.47 (95% confidence interval (CI) 1.28–4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI 0.44–2.09) in the highest total estradiol quartile; p interaction = 0.04). The main conclusion was that women with lower pretreatment endogenous estrogen levels were at greater risk for breast cancer during E+P therapy compared with those with higher levels.

Comment

Once again, the WHI investigators scratch the floor of their database and produce additional, detailed results, which shed more light on the debated association of HT and risk for breast cancer. Their analyses confirm previous reports that higher baseline levels of total estradiol, bioavailable estradiol, estrone and estrone sulfate are associated with higher breast cancer risk in postmenopausal women. In addition, they found that there is an association between pretreatment blood levels of female sex hormones and risk for subsequent breast cancer later on while taking hormones. Hormone users in quartile 4, having a pretreatment estradiol level of 15 pg/ml or higher, did not have an increased risk for breast cancer compared to the placebo group. Women with pretreatment estradiol levels between 15 and 8 pg/ml (quartiles 2, 3) had a non-significant increase in risk for breast cancer, and only those with basal estradiol of 8 pg/ml or less (quartile 1) demonstrated a significant increase in breast cancer risk (OR 2.47, 95% CI 1.28–4.79).

The question arising from these data is the reasoning for such an association. The easiest way to explain it lies in the known risk factor for breast cancer – obesity. A recent release from the WHI 'kitchen', combining the clinical and observational studies, demonstrated once again a significant association between weight and breast cancer, in line with results of many previous trials [2]. The strength of those WHI findings lies in its numbers: the study included 147,202 women ages 50–79, who were followed for a mean 8 years. On the other hand, the association between anthropometric parameters, primarily body mass index (BMI), and endogenous estradiol, has been well documented as well [3]. Obese women have higher endogenous estradiol levels and lower SHBG levels, which is attributed to the enhanced conversion of androgens to estrogen in the fatty tissue. In addition, there is evidence to show a negative correlation between BMI and the effect of estrogens on breast cancer risk [4]. The famous collaborative re-analysis from 1997 found that the relative breast cancer risk associated with HT decreased progressively with increasing BMI, a BMI of 25 kg/m2 being the turning point that marked the no-risk zone [5]. So all it takes now is to add 1 + 1 to get 2, namely, that postmenopausal woman with higher pretreatment estradiol levels are likely to be obese and have a higher basal risk for breast cancer, and as such are not exposed to further increase in breast cancer risk while on hormone therapy. This nice and simple explanation would be plausible, but, in fact, the current WHI pretreatment sex hormone data were adjusted for BMI and therefore the above reasoning may not hold and other mechanisms should be sought. Anyway, as the WHI investigators write, pretreatment determination of estradiol levels may be helpful in identifying women at particularly elevated risk for breast cancer with combined hormone therapy.
Amos Pines
Department of Medicine 'T', Ichilov Hospital, Tel-Aviv, Israel

References

1. Farhat GN, Parimi N, Chlebowski RT, et al. Sex hormone levels and risk of breast cancer with estrogen plus progestin. J Natl Cancer Inst 2013 Sep 16. Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/24041978 

2. Hartz AJ, He T. Cohort study of risk factors for breast cancer in post menopausal women. Epidemiol Health 2013;35:e2013003.
http://www.ncbi.nlm.nih.gov/pubmed/23682336 

3. Baglietto L, English DR, Hopper JL, et al. Circulating steroid hormone concentrations in postmenopausal women in relation to body size and composition. Breast Cancer Res Treat 2009;115:171–9.
http://www.ncbi.nlm.nih.gov/pubmed/18509757 

4. Kuhl H. Breast cancer risk in the WHI study: the problem of obesity. Maturitas 2005;51:83-97.
http://www.ncbi.nlm.nih.gov/pubmed/15883113

5. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies with 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047–59.
http://www.ncbi.nlm.nih.gov/pubmed/10213546